Thrombocytopenia is a disease that accompanies immunological disorders or bone marrow damaging metastatic tumors, tuberculosis, leukemia, etc. Alternatively, it is caused by other factors such as the use of chemotherapeutics or radiation therapy. Thrombocytopenia is a serious disease which, when aggravated, causes bleeding in various parts of the body, occasionally leading to death.
Symptomatic therapy by platelet transfusion is currently considered to be the sole reliable method that can treat thrombocytopenia and it is desired to develop therapeutics that can increase platelets per se.
In recent years, reports have been made that show the platelet increasing action of cytokines such as interleukin-6, interleukin-11 and leukemia inhibitory factor (LIF) (Ishibashi et al., Blood, 74:1241-1244, 1989; Asano et al., Blood, 75:1602-1605, 1990; Zenji Okada et al., KETUEKI SHUYOKA, 22:23-31, 1991). However, the production of these cytokines is regulated and controlled by various cells within the body and if they are externally administered to the body, the balance in regulation is upset, eventually causing serious side effects such as damage to the liver.
It has also been suggested recently that a protein called "thrombopoietin (TPO)" is a factor that increases megakaryocytes and platelets (see, for example, Sauvage et al., Nature, 369:533-538, 1994), however, clinical effects of this protein have not yet been verified.
Derivatives such as muramyl dipeptide are known as low-molecular weight compounds that increase the platelet count (Nakajima et al., Arzneim.-Forsch./Drug Res. 41:60-65, 1989). It is postulated that these derivatives increase platelets by activating monocytes and macrophages so as to produce interleukin-6. However, it has also been reported that the administration of derivatives such as muramyl dipeptide also triggers other physiological activities based on the activation of macrophages, thereby causing fever and other side effects (NIHON IGAKU HOSHASEN GAKKAISHI, 48(4):514, 1988).
The compounds structurally similar to the compounds of the invention are taught in Japanese Patent Public Disclosure Nos. 304893/1989 and 186/1990, as well as The Journal of Antibiotics, 42:1331-1343, 1989; they are 2-pyranone derivatives obtained as the metabolites of actinomyces of the genus Streptomyces and these compounds have been reported to have an antimicrobial action against plant pathogenic fungi, as well as cytotoxicity to leukemic cells.
In addition, Japanese Patent Public Disclosure Nos. 213758/1993 and 2886/1995 teach that 2-pyranone derivatives are compounds exhibiting a platelet increasing action in mouse. However, these compounds are not necessarily satisfactory in terms of safety.
An object of the invention is to overcome the aforementioned defects of the prior art by providing compounds that are safe and which have an action for increasing platelets per se.